title: A genetically engineered oncolytic adenovirus decoys and lethally traps quiescent cancer stem-like cells in S/G2/M phases.
abstract: OBJECTIVE
  Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem-like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem-like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem-like cells.
  
  
  METHODS
  We established CD133(+) cancer stem-like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent cancer stem-like cells. We visualized the treatment dynamics of OBP-301 killing of quiescent cancer stem-like cells in dormant tumor spheres and xenografts using a fluorescent ubiquitination cell-cycle indicator (FUCCI).
  
  
  RESULTS
  CD133(+) gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133(+) cancer stem-like cells resistant to chemoradiotherapy. OBP-301 induced cell-cycle mobilization from G0-G1 to S/G2/M phases and subsequent cell death in quiescent CD133(+) cancer stem-like cells by mobilizing cell-cycle-related proteins. FUCCI enabled visualization of quiescent CD133(+) cancer stem-like cells and proliferating CD133(-) non-cancer stem-like cells. Three-dimensional visualization of the cell-cycle behavior in tumor spheres showed that CD133(+) cancer stem-like cells maintained stemness by remaining in G0-G1 phase. We showed that OBP-301 mobilized quiescent cancer stem-like cells in tumor spheres and xenografts into S/G2/M phases where they lost viability and cancer stem-like cell properties and became chemosensitive.
  
  
  CONCLUSIONS
  Oncolytic adenoviral infection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent cancer stem-like cells.
authors.affiliation: Authors' Affiliations: Department of Gastroenterological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences; Center for innovative clinical medicine, Okayama University Hospital, Okayama; Oncolys BioPharma, Inc., Tokyo, Japan; Department of Surgery, University of California San Diego; and AntiCancer, Inc., San Diego, California.
authors.forename: Shuya
authors.initials: S
authors.lastname: Yano
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tazawa
authors.forename: Yuuri
authors.initials: Y
authors.lastname: Hashimoto
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Shirakawa
authors.forename: Shinji
authors.initials: S
authors.lastname: Kuroda
authors.forename: Masahiko
authors.initials: M
authors.lastname: Nishizaki
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kishimoto
authors.forename: Futoshi
authors.initials: F
authors.lastname: Uno
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagasaka
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Urata
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Kagawa
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.forename: Toshiyoshi
authors.initials: T
authors.lastname: Fujiwara
mesh_terms: D000071916:AC133 Antigen; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology; D059447:Cell Cycle Checkpoints; D045744:Cell Line, Tumor; D002470:Cell Survival; D002945:Cisplatin / Q000494:pharmacology; D005260:Female; D005818:Genetic Engineering; D006023:Glycoproteins / Q000378:metabolism; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D008819:Mice, Nude; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D014411:Neoplastic Stem Cells / Q000502:physiology* / Q000821:virology; D050504:Oncolytic Viruses / Q000235:genetics*; D017239:Paclitaxel / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism; D011836:Radiation Tolerance; D059008:Time-Lapse Imaging; D047368:Tumor Burden; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; D006023:Glycoproteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606024:Prom1 protein, mouse; D017239:Paclitaxel; D002945:Cisplatin